U.S. Pat. No. 4,007,270 to Bernstein et al. discloses that aurintricarboxylic acid (ATA) and certain of its derivatives and salts are useful as complement inhibitors which play an important role as mediators in immune, allergic, immunochemical and immunopathological reactions. The patent discloses a method of inhibiting the complement system in blood serum subjecting the serum to aurintricarboxylic acid or its derivatives or salts and that ATA has anti-inflammatory properties.
U.S. Pat. No. 4,880,788 to Moake et al. discloses a method for preventing and treating thrombosis. Moake et al. suggest that aurintricarboxylic acid may prevent yon Willebrand Factor mediated aggregation or agglutination of platelets and thereby prevents for formation of thromboemboli.
Cushman, M. et al. "Preparation and Anti-HIV Activities of Aurintricarboxylic Acid Fractions and Analogues: Direct Correlation of Antiviral Potency with Molecular Weight", J. Med. Chem., Volume 34, (1991) pp. 329-337, disclose that aurintricarboxylic acid (ATA) binds to small gp120 in the absence of CD4 binding and is sufficient for anti-HIV activity.
Cushman, M. et al., "Synthesis and Anti-HIV Activities of Low Molecular Weight Aurintricarboxylic Acid Fragments and Related Compounds", J. Med. Chem., Volume 34, (1991) pp. 337-342, disclose derivatives of aurintricarboxylic acid and their ability to afford protection against the cytopathogenicity of HIV-2 in MT-4 cell and HIV-1 in CEM cells. Two derivatives of ATA were found to inhibit syncytium formation. In contrast to ATA itself, two of the derivatives of ATA were inactive when tested for prevention of the binding of the OKT4A monoclonal antibody to the CD4 receptor and also for the inhibition of HIV-1 reverse transcriptase. It was concluded by Cushman et al. that these derivatives appear to act by a mechanism that is distinct from that of polymeric ATA. Cushman et al. do not disclose a method of use of aurintricarboxylic acid or its analogues or derivatives as an anti-angiogenic agent.
Gonzalez, R. G. et al. "Fractionation and Structural Elucidation of the Active Components of Aurintricarboxylic Acid, a Potent Inhibitor of Protein Nucleic Acid Interactions". Biochimica et Biophysica Acta, Volume 562, (1979) pp. 534-545, disclose that the triphenylmethane dye, aurintricarboxylic acid, is a potent inhibitor of protein-nucleic acid interactions. Gonzalez et al. noted that the degree of inhibitory activity of the aurintricarboxylic acid preparation depends on the degree of polymerization of the aurintricarboxylic acid polymer. The experimentation examined the ability of three fractions of ATA to inhibit DNA-poly L-lysine complex formation. Two biologically relevant assays were used based on the binding of polyribouridylic acid to ribosomal S1 and to E. coli 70-S ribosomes. The Gonzalez et al. publication noted that studies have eluded to the variable activity of commercial ATA preparations and that the commonly accepted structure of ATA might not be the true inhibitor of protein-nucleic acid interactions.
Mellon, W. S "Inhibitory Action of Aurintricarboxylic Acid and Rifamycin AF/013 at the Polynucleotide Domain of 1,25-Dihydroxyvitamin D.sub.3 -Receptor Complexes", Biochemical Pharmacology, Volume 33, Number 7, (1984) pp. 1047-1057, discloses that the binding of 1,25-dihydroxyvitamin D.sub.3 -receptor complexes from chicken intestine to DNA-cellulose and isolated intestinal nuclei is inhibited in a dose-dependent manner by ATA and rifamycin AF/013, which are known polymerase inhibitors. Mellon concluded that the observed inhibition was caused by ATA directly inhibiting the receptor. Mellon suggests that the receptor and polymerases have corresponding properties, but states that the question remains whether this is an insubstantial similarity or it is structurally relevant to hormone action.
Moudgil, V. K. et al. "Modulation of DNA Binding of Glucocorticoid Receptor by Aurintricarboxylic Acid", J. Steroid Biochem., Volume 23, Number 2, (1985) pp. 125-132, disclose that ATA is an inhibitor of the DNA-binding of rat liver glucocorticoid-receptor complex. They found that treatment with ATA did not appear to alter the steroid binding properties of the receptor or accelerate dissociation of the complex. Moudgil et al. concluded that ATA does not inhibit the process of receptor activation and that it may act via interaction with the DNA-binding sites at the glucocorticoid-receptor. They suggest that the interaction may result in an alteration in the conformation of the activated receptor to a form unfavorable for optimum DNA-binding. They suggest that the skeletal structure of triphenylmethane, rather than the side chains, is the site of inhibitory action of ATA. Moudgil et al. reserve that the evidence presented in their study only indirectly argues in favor of an interaction between ATA and the glucocorticoid-receptors and that further studies are required to confirm the interaction.
Nakane, H. et al. "Differential Inhibition of various Deoxyribonucleic Acid Polymerases by Evans Blue and Aurintri-carboxylic Acid", Eur. J. Biochem., Volume 177, (1988) pp. 91-96, disclose that both Evans blue and ATA exhibited inhibitor effects on the in vitro activity of all DNA polymerases, including human DNA polymerases, .alpha., .beta., .tau., DNA primase, calf-thymus terminal deoxynucleotidyltransferase, RLV reverse transcriptase, E. coli DNA polymerase 1, and RNA polymerase.
Skidmore, A. F. et al. "Characterization and Use of the Potent Ribonuclease Inhibitor Aurintricarboxylic Acid for the Isolation of RNA from Animal Tissues", Biochem. J., Volume 263, (1989) pp. 73-80, disclose studies of ATA which yield that it is very useful as an RNAase inhibitor.
Schols, D. et al., "Specific Interaction of Aurintricarboxylic Acid with the Human Immunodeficiency Virus/CD4 Cell Receptor", Proc. Natl. Acad. Sci. USA, Volume 86, (May 1989) pp. 3322-3326, disclose that ATA is a compound that affects a rapid and selective modulation of CD-4 receptor expression on T4.sup.+ cells without affecting the expression of other cell-surface markers. Schols et al. suggest that the exact mechanism by which ATA blocks a CD-4 receptor remains unknown but the anionic character of ATA suggests that ATA should be able to bind to lysine and/or arginine residues. Strony, J. et al. "Aurintricarboxylic Acid in a Canine Model of Coronary Artery Thrombosis", Circulation, Volume 81, Number 3, (March 1990) pp. 1106-1114, disclose that ATA is unique in its inhibition of glycoprotein Ib-mediated platelet adhesion and subsequent aggregation. Strony et al. suggest that platelet glycoprotein Ib-von Willebrand factor interactions are important during coronary occlusion and that ATA can inhibit coronary thrombosis associated with coronary constriction. Strony et al. do not state that the inhibition of coronary occlusion is due to anti-angiogenic properties of ATA.
Benezra, M. et al. "Reversal of Basic Fibroblast Growth Factor-mediated Autocrine Cell Transformation by Aromatic Anionic Compounds", Cancer Research, Volume 52, (Oct. 15, 1992) pp. 5656-5662, disclose that ATA binds to basic fibroblast growth factor. Benezra et al. disclose that a common feature of compounds such as ATA and other dyes is their ability to mimic many of the biological effects of heparin such as anti-coagulation, release of ECM-bound bFGF, inhibition of heparanase activity and interaction with lipoprotein lipase. The study suggests that the effect of ATA may not be due to the actual interaction with bFGF, suggesting that ATA may function by blocking the participation of bFGF in an intracellular autocrine pathway.
Kan, M. et al. "An Essential Heparin-binding Domain in the Fibroblast Growth Factor Receptor Kinase", Science, Volume 259, (Mar. 26, 1993) pp. 1918-1921, disclose that heparin or heparin-like heparan sulfate proteoglycans are necessary for activity of the heparin-binding fibroblast growth factor family. Heparin interacts independently of the FGF ligand with a specific sequence (K18K) in one of the immunoglobulin-like loops in the extracellular domain of the FGF receptor tyrosine kinase transmembrane glycoprotein. Kan et al. found that a synthetic peptide corresponding to the K18K inhibited heparin and heparin dependent FGF binding to the receptor.
Bouck, N. "Tumor Angiogenesis: The Role of Oncogenes and Tumor Suppressor Genes", Cancer Cells, Volume 2, Number 6, (June 1990) pp. 179-185, discloses that the progressive growth of solid tumors is strictly dependent on their ability to attract new blood vessels that will supply them with oxygen and essential nutrients. Angiogenesis has been shown to precede or accompany malignancy. The focus of Bouck's study was to confirm that suppressor gene loss can influence angiogenesis. Bouck conjectures that molecules produced by normal cells that block angiogenesis may be helpful in combating tumor growth and the molecules produced by tumor cells that promote angiogenesis may be useful targets for anti-tumor drugs.
Gagliardi, A. et al. "Inhibition of Angiogenesis by Suramin", Cancer Research, Volume 52, (Sep. 15, 1992) pp. 5073-5075, disclose the ability of suramin to inhibit anglogenesis in chick chorioallantoic membrane. Gagliardi et al. disclose that suramin alone inhibited anglogenesis, and potentiated the activity of angiostatic steroids. Weisz, P. B. et al., "Anglogenesis and Heparin Mimics", Anglogenesis: Key Principles--Science--Technology--Medicine, (eds. R. Steiner, P. B. Weisz & R. Langer), (1992) pp. 107-117, disclose that glycosaminoglycans, such as heparin, can modulate angiogenesis and that this modulation varies greatly among varying heparin production lots and thus in glycosaminoglycans of different chemical structure.
Folkman, J. et al. "Angiogenesis Inhibition and Tumor Regression Caused by Heparin or a Heparin Fragment in the Presence of Cortisone", Science, Volume 221, (Aug. 19, 1983) pp. 719-725, disclose the inhibitory effect of heparin-cortisone.
Allain et al., "Mise en evidence de l'action anti-inflammatoire de l'alumninon ou acide aurine triboxylique", C. R. Seances Soc. Biol. Fil, Volume 174, (1980) pp. 68-73, disclose that aurintricarboxylic acid reduces Freund adjuvant-induced arthritis and carageen-induced oedemas in the paws of rats. Allain et al. do not disclose that aurintricarboxylic acid has anti-angiogenic properties but disclose the use of aurintricarboxylic acid as an anti-inflammatory agent for the treatment of arthritis.